SignificanceApproximately 1 in 100 people have epilepsy, and nearly 3% of epileptics have photosensitive epilepsy, which results in serious debilitating seizures. Despite these numbers, in 100 y of research, no clear single gene defect has been shown to be causative in photosensitive epilepsy in genetic models. Although sphingolipid defects have been shown to be causative for many lysosomal storage diseases in humans as well as animal models, our study shows an important connection to a neuronal disease, photosensitive epilepsy, using the fly system as a model. We show that in a Drosophila ceramide phosphoethanolamine synthase-null mutant cortical glial cells fail to establish plasma membrane processes required to encapsulate neuronal cell bodies, resulting in photosensitive epilepsy.

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Metabolomics follows the changes in concentrations of endogenous metabolites, which may reflect various disease states as well as systemic responses to environmental, therapeutic, or genetic interventions. In this study, we applied metabolomic approaches to monitor dynamic changes in plasma and urine metabolites, and compared these metabolite profiles in Eisai hyperbilirubinemic rats (EHBR, an animal model of cholestasis) with those in the parent strain of EHBR - Sprague-Dawley (SD) rats - in order to characterize cholestasis pathophysiologically. Ultra-performance liquid chromatography/tandem mass spectrometry-based analytical methods were used to assay metabolite levels. More than 250 metabolites were detected in both plasma and urine, and metabolite profiles of EHBR differed from those of SD rats. The levels of antioxidative and cytoprotective metabolites, taurine and hypotaurine, were markedly increased in urine of EHBR. The levels of many bile acids were also elevated in plasma and urine of EHBR, but the extent of elevation depended on the particular bile acid. The levels of cytoprotective ursodeoxycholic acid and its conjugates were markedly elevated, while that of cytotoxic chenodeoxycholic acid remained unchanged, suggesting the balance of bile acids had shifted resulting in decreased toxicity. In EHBR, reduced biliary excretion leads to increased systemic exposure to harmful compounds including some endogenous metabolites. Our metabolomic data suggest that mechanisms exist in EHBR that compensate for cholestasis-related damage.

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